Significance StatementAlthough both short-acting and long-acting erythropoietin-stimulating agents (ESAs) are used to treat anemia in patients undergoing hemodialysis, the relative effects on survival of these ESA types are unknown. In this nationwide, registry-based cohort study enrolling 194,698 patients on hemodialysis, the authors found that long-acting ESA users showed a 13% higher rate of death than short-acting ESA users (P<0.001) during the 2-year follow-up period. The difference in risk was pronounced among patients receiving high doses of ESA, for whom the adjusted 2-year number needed to harm for death was 30.8. Survival of long-acting ESA users who achieved more optimal hemoglobin levels was inferior to that of short-acting ESA users. Among patients on hemodialysis, long-acting ESA use might be associated with an increased rate of death compared with short-acting ESA use.BackgroundDespite the widespread use of erythropoietin-stimulating agents (ESAs) to treat anemia in patients undergoing hemodialysis, the relative mortality risks associated with use of different types of ESAs are unknown.MethodsTo compare the mortality risk associated with use of short-acting ESAs versus long-acting ESAs, we conducted a nationwide cohort study of 194,698 hemodialysis patients in Japan who received either a short-acting (epoetin α/β or epoetin κ) or a long-acting (darbepoetin or epoetin β pegol) ESA. Study outcomes were 2-year all-cause and cause-specific mortality. In addition to Cox proportional hazards models, we performed an instrumental variable analysis in which facility-level long-acting ESA prescription rates were taken as the instrumental variable.ResultsDuring the 2-year follow-up period, 31,557 deaths occurred. In a multivariable Cox model, long-acting ESA users had a 13% higher rate of deaths compared with short-acting ESA users, a significant difference (P<0.001). Similar results were obtained in other analyses. This difference in risk was pronounced among patients receiving high doses of ESA (for whom the adjusted 2-year number needed to harm for death was 30.8). Long-acting ESA use was associated with an increased rate of death from cardiovascular diseases, infection, and malignancies. In the instrumental variable analysis, long-acting ESA users remained at a significantly higher risk of death. Compared with anemic (hemoglobin 9.0–9.9 g/dl) short-acting ESA users, long-acting ESA users who achieved more optimal hemoglobin levels (10.0–10.9 g/dl) showed a higher mortality rate.ConclusionsAmong patients undergoing hemodialysis, use of long-acting ESAs might be associated with a higher risk of death than use of short-acting ESAs.